DESCRIPTION (Taken from the applicant's Abstract) The broad objective of this proposal is to foster the development of an independent and productive investigator in the area of molecular and developmental biology of the gastrointestinal tract. The long term research goal of this proposal is to understand the molecular mechanisms regulating the maturational decline in intestinal lactase gene transcription. Intestinal lactase is the enterocyte disaccharidase responsible for digestion of lactose, the primary carbohydrate in milk. Lactase activity is maximal prior to weaning and then declines significantly during maturation. Decreased lactase activity combined with excessive milk consumption results in symptoms of carbohydrate malabsorption in most mature mammals, including humans. The mechanisms involved in regulating this maturational decline in intestinal lactase activity have not been fully defined. Recent reports suggest that control of the decline in lactase is primarily at the level of gene transcription. In addition, our preliminary data suggest that a lactase promoter cis element is bound differentially during intestinal maturation by at least two distinct nuclear proteins. Our hypothesis, based on this data, is that the maturational decline in lactase expression is mediated by differential interaction between its promoter and specific nuclear transcription factors. Specific research objectives, therefore, are aimed at characterization of lactase gene regulatory elements and identification of nuclear proteins interacting with those elements. We aim to characterize the lactase DNA regulatory elements by analyzing expression of genomic deletions linked to a reporter gene and expressed in transgenic mice. We will identify nuclear proteins interacting with lactase gene fragments using DNase I hypersensitivity, footprint, and gel shift assays. We aim to functionally characterize the proteins by altering their expression in cell culture and in transgenic mice and assaying for transcriptional activity. The candidate, having delineated an area of research inquiry, will conduct the research with the advice and guidance of a mentor in the field of developmental biology. The research experience, supplemented with coursework and seminars in the fields of molecular and developmental biology, will provide the candidate with the tools needed to transition to a career as an independent and productive scientist performing research on the molecular biology of intestinal development.